Among compounds having a pyridonecarboxylic acid as base skeleton, there have been known many compounds, which are useful synthetic antibacterial agents, by virtue of their excellent antibacterial activity and broad antibacterial spectrum. Among such compounds, compounds such as norfloxacin (see Patent Document 1), enoxacin (see Patent Document 2), ofloxacin (see Patent Document 3), ciprofloxacin (see Patent Document 4), and tosufloxacin (Patent Document 5) are extensively used in clinical application as therapeutic agents for infectious diseases. However, these compounds are still unsatisfactory in terms of, for example, antibacterial activity, intestinal absorption, metabolic stability, and side effects; particularly phototoxicity and cytotoxicity.
The present inventors previously conducted extensive studies in order to solve the aforementioned problems, and found that, pyridonecarboxylic acid derivatives having a substituted pyridyl group at the 1-position of the pyridonecarboxylic acid moiety, especially those having an aminoazetidinyl group at the 7-position of the pyridonecarboxylic acid moiety, have remarkably excellent characteristics; i.e. exhibit remarkably potent antibacterial activity, and, unlike most of pyridonecarboxylic acid class of synthetic antibacterial agents, do not produce phototoxicity (Patent Documents 6 and 7).
Another requirement for drugs to perform their abilities efficiently on the treatment of infectious diseases is high bioavailability of the drugs, more preferably, a higher blood level of the free form of drugs. This latter property is closely related to binding of the drug to serum proteins. That is, the drug with lower binding rate to serum proteins results in higher proportion of free form of the drug in the blood. Therefore, a drug exhibiting higher bioavailability and lower binding rate to serum proteins is a more preferred therapeutic agent for infectious diseases.
The pyridonecarboxylic acid derivative having a substituted pyridyl group at the 1-position and an aminoazetidinyl group at the 7-position is improved its bioavailability by introducing an alkyl group to the amino group on the azetidine ring and increasing the number of carbon atoms of the alkyl group so as to enhance lipophilicity of the derivative. However such modification is also prone to enhance the binding rate of the derivative to serum proteins.
Patent Document 1: Japanese Patent Application Laid-Open (kokai) No. 53-141286
Patent Document 2: Japanese Patent Application Laid-Open (kokai) No. 55-031042
Patent Document 3: Japanese Patent Application Laid-Open (kokai No. 57-046986
Patent Document 4: Japanese Patent Application Laid-Open (kokai) No. 58-076667
Patent Document 5: Japanese Patent Application Laid-Open (kokai) No. 60-228479
Patent Document 6: WO 97/11068 Pamphlet
Patent Document 7: WO 01/02390 Pamphlet